Molecular physiology and regulation of presynaptic calcium channels

CaV2.1 and CaV2.2 channels (‘CaV2.x’) mediate most synaptic transmission.

They convert electrical signals (action potentials) to Ca2+ entry at the presynaptic terminal, triggering transmitter release.

CaV2.x sense and respond to action potentials by the action of functionally diverse voltage-sensing domains, four in each channel protein. Moreover, voltage-dependent CaV2.x opening is regulated by previous excitation. Despite their critical role in neurophysiology, CaV2.x function and regulation remain obscure.

This limits our knowledge of fundamental synaptic physiology and hinders the design of CaV2.x-targeting drugs, e.g., against severe CaV2.1-channelopathies or chronic pain.We will apply a cutting-edge approach to human CaV2.x channels, voltage-clamp fluorometry, which allows the optical tracking of protein structural dynamics under physiologically-relevant conditions and diverse regulation regimes.

Specifically, we will: (1) identify the molecular transitions underlying CaV2.x voltage-dependent opening and lead to transmitter release; (2a) characterize CaV2.x inactivation, a type of ‘molecular memory’ which contributes to short-term synaptic depression; (2b) determine how Ca2+ potentiates CaV2.1, promoting short-term synaptic facilitation; (2c) understand how transmitters inhibit CaV2.2 to evoke synaptic inhibition.

Supported by exciting preliminary data, our studies will address decades-old questions in molecular neurophysiology and support next-generation drug design.